Identification of High-Affinity P2Y₁₂ Antagonists Based on a Phenylpyrazole Glutamic Acid Piperazine Backbone

A series of novel, highly potent P2Y₁₂ antagonists as inhibitors of platelet aggregation based on a phenylpyrazole glutamic acid piperazine backbone is described. Exploration of the structural requirements of the substituents by probing the structure–activity relationship along this backbone led to the discovery of the <i>N</i>-acetyl-(<i>S</i>)-proline cyclobutyl amide moiety as a highly privileged motif. Combining the most favorable substituents led to remarkably potent P2Y₁₂ antagonists displaying not only low nanomolar binding affinity to the P2Y₁₂ receptor but also a low nanomolar inhibition of platelet aggregation in the human platelet rich plasma assay with IC₅₀ values below 50 nM. Using a homology and a three-dimensional quantitative structure–activity relationship model, a binding hypothesis elucidating the impact of several structural features was developed